(Applicant's abstract) The research objectives of the Center for Study of Opioid Receptors and Drugs of Abuse are to gain insights into the mechanisms of action of opioid drugs and their receptors with the ultimate goal of discerning molecular processes that contribute to opiate addiction, tolerance and withdrawal. The Center has four integrated components which have evolved since the cloning of the opioid and ORL-1 receptors. These components will investigate the actions and regulation of receptors both in vitro and in vivo utilizing overlapping methodologies and resources. The Center will specifically investigate: 1) The coupling of opioid and ORL-1 receptors through G-proteins and second messenger systems to the release process, with an emphasis on the contribution of specific calcium channel subtypes. 2) The role of receptor internalization in the regulation of receptors and the functional consequences of drugs that induce sequestration (i.e. enkephalins) versus those that do not (i.e. morphine). 3) The role of ORL-1 receptor ligands and their interaction with opiate drugs in the modulation of hippocampal function. 4) Whether ORL-1 receptor agonists have "anti-opioid" effects on brain reward systems. To facilitate the research, the Center has an Administrative Core and five Scientific Cores which serve to integrate its resources, as well as provide practical expertise in specific technical areas. The Scientific Cores cover Molecular Biology, Peptide Chemistry, Analytical Neurochemistry, Tissue Culture and Imaging of both antibody and nucleic acid probes. The continued application of this multidisciplinary and collaborative approach is enhancing our understanding of the molecular mechanisms underlying the addiction process and thus provides a basis for improved clinical methods for ameliorating the problems associated with drugs of abuse.